title: The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo.
abstract: Podocyte injury, a major contributor to the pathogenesis of diabetic nephropathy, is caused at least in part by the excessive generation of reactive oxygen species (ROS). Overproduction of superoxide by the NADPH oxidase isoform Nox4 plays an important role in podocyte injury. The plant extract silymarin is attributed antioxidant and antiproteinuric effects in humans and in animal models of diabetic nephropathy. We investigated the effect of silybin, the active constituent of silymarin, in cultures of mouse podocytes and in the OVE26 mouse, a model of type 1 diabetes mellitus and diabetic nephropathy. Exposure of podocytes to high glucose (HG) increased 60% the intracellular superoxide production, 90% the NADPH oxidase activity, 100% the Nox4 expression, and 150% the number of apoptotic cells, effects that were completely blocked by 10 μM silybin. These in vitro observations were confirmed by similar in vivo findings. The kidney cortex of vehicle-treated control OVE26 mice displayed greater Nox4 expression and twice as much superoxide production than cortex of silybin-treated mice. The glomeruli of control OVE26 mice displayed 35% podocyte drop out that was not present in the silybin-treated mice. Finally, the OVE26 mice experienced 54% more pronounced albuminuria than the silybin-treated animals. In conclusion, this study demonstrates a protective effect of silybin against HG-induced podocyte injury and extends this finding to an animal model of diabetic nephropathy.
authors.affiliation: Univ. of Texas Health Science Center, Dept. of Medicine, Division of Nephrology MC 7882, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
authors.forename: Khaled
authors.initials: K
authors.lastname: Khazim
authors.forename: Yves
authors.initials: Y
authors.lastname: Gorin
authors.forename: Rita Cassia
authors.initials: RC
authors.lastname: Cavaglieri
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.forename: Paolo
authors.initials: P
authors.lastname: Fanti
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005947:Glucose / Q000494:pharmacology*; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D050199:Podocytes / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077385:Silybin; D012838:Silymarin / Q000627:therapeutic use*; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D012838:Silymarin; D013481:Superoxides; D000077385:Silybin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D005947:Glucose
keywords: NADPH oxidase; albuminuria; apoptosis; diabetic nephropathy; phytochemicals